Search

The purpose of this study is to test the hypothesis that rapidly dissolving immediate-release (IR) solid oral products containing a highly soluble and highly permeable drug [biopharmaceutical classification system (BCS) class I] are bioequivalent under fed conditions. Metoprolol and propranolol (BCS class I) as well as hydrochlorothiazide (BCS class III) were selected as model drugs. The relative bioavailability of two FDA approved (Orange Book AB rating) solid oral dosage forms of metoprolol and propranolol/hydrochlorothiazide (combination tablets) was evaluated in human volunteers under fed conditions using a two-way crossover design. Equal numbers of male and female volunteers were recruited, and racial and/or ethnic minorities were not excluded. The plasma concentrations of metoprolol, propranolol, and hydrochlorothiazide were determined using validated high-performance liquid chromatography (HPLC) methods. Eighteen subjects completed the metoprolol study while 17 subjects completed the propranolol/hydrochlorothiazide combination tablet study. In the metoprolol study, the 90% confidence intervals of Cmax and AUCinf were 98−118% and 92−115%, respectively. For propranolol, the 90% confidence intervals of Cmax and AUCinf were 91−121% and 89−117%, and for hydrochlorothiazide, the 90% confidence intervals for Cmax and AUCinf were 96−107% and 97−106%, respectively. These study results appear to support the hypothesis that rapidly dissolving IR solid oral products containing a BCS class I drug are likely to be bioequivalent under fed conditions. In addition, BCS class III drugs may have the potential to be bioequivalent under fed conditions. Keywords: BCS; food effect; HPLC; metoprolol; propranolol; hydrochlorothiazide

The pharmacokinetics and associated pharmacodynamics of nifedipine were studied at steady state in 12 patients with angina pectoris who were receiving nifedipine 10–40 mg tid. After dosing, serum nifedipine concentrations rose rapidly and decayed in a log‐linear fashion. The mean (± SEM) maximum serum concentration (Cmax) after dose normalization, and the time to Cmax(tmax) were 115 ± 7 ng/mL and 0.72 ± 0.13 hr, respectively. The mean area under the plasma concentration‐time curve per 10‐mg dose was 304 ± 34 hr‐ng/mL. The average elimination rate constant was 0.205 ± 0.016 hr, and the harmonic mean elimination half‐life was 3.4 hr (range, 2.5‐4.9 hr). Heart rate increased (5–6 beats/min, P < .05) from baseline for up to one hour after dose, while mean diastolic blood pressure decreased (6–15 mm Hg, P < .05) for up to four hours. Cardiac output was increased (1.1–2.8 L/min, P < .05), and calculated total systemic resistance (3.6‐6.3 mm Hg/L/min, P < .05) was decreased for the entire dosing interval after nifedipine dosing. Hysteresis plots for heart rate and mean diastolic blood pressure showed a time lag between changes in serum nifedipine concentrations and heart rate, but not between serum nifedipine concentrations and blood pressure. Changes in cardiac output did not correlate with serum nifedipine concentrations. The steady‐state kinetic and dynamic parameter values in patients with angina pectoris in this study were similar to those found in healthy volunteers or hypertensive patients after acute nifedipine administration. Interpatient variability in pharmacokinetics and hemodynamic responses to nifedipine, rather than the underlying cardiovascular disease, would require titration of nifedipine doses to patient response.

The protein binding of salicylate was measured by continuous ultrafiltration (diafiltration) at 22°C in serum obtained from 5 healthy young (mean age: 27 years) and 5 healthy elderly (mean age: 73 years) male volunteers. Unbound salicylate increased disproportionately with increasing total salicylate concentration, up to 7000 µmol, in all sera. The fraction bound of salicylate was significantly lower in sera from elderly but this was not due to decreased albumin or total protein concentrations. The binding of salicylate to serum proteins was characterized by two classes of binding sites. The high affinity site had an association constant of either 94901/mol (young) or 75601/mol (elderly) and the number of binding sites was either 4.7 (young) or 3.7 (elderly). The total binding capacity of the low affinity site, 1121/mol, in sera from elderly was significantly less than the binding capacity, 631l/mol, in sera from young. Differences in binding capacity of the low affinity site partially accounted for a two to three-fold increase in the salicylate free fraction in elderly sera. These data suggest that age-related differences in serum protein binding may influence salicylate pharmacokinetics.

The single and multiple dose pharmacokinetics of oral nifedipine capsules, 10 mg, have been examined in five patients with peripheral vasospasm. After a single dose, nifedipine was rapidly absorbed in three and slowly absorbed in two patients. Mean bioavailability parameters included a tmaxof 2.9 h, a Cmaxof 33.3 ng ml−1and a AUC0–8 hof 113.3 ngh ml−1. After multiple dosing with either 10 or 20 mg every 8 h for 10 days the mean tmaxat steady state was 2.1 h while the mean dose-corrected (to 10 mg) Cmaxand AUC0–8 hwere 51.9 ng ml−1and 146.9 ngh ml−1, respectively. The mean elimination rate constant was 0.173 h−1after both single and multiple doses. The mean extent of accumulation of nifedipine, defined as the ratio of AUC0–8 h(steady state)/AUC0–8 h(single dose), was 1.3; we concluded that nifedipine accumulates in the body when it is administered every 8 h. This should be taken into account when predicting steady state serum concentrations and haemodynamic effects of nifedipine from single dose kinetic data.

A rapid, sensitive, and specific method of analysis for mezlocillin in serum and urine by high-pressure liquid chromatography is described. A solid-phase extraction column was used to remove interfering substances from samples before chromatography. Quantitation included the use of an internal standard, nafcillin. Mezlocillin was chromatographed with a phosphate buffer-acetonitrile (73:27) mobile phase and a C-18 reverse-phase column and detected at a wavelength of 220 nm. The assay had a sensitivity of 1.6 micrograms/ml and a linearity of up to 600 micrograms/ml and 16 mg/ml in serum and urine, respectively, with only 0.1 ml of sample. The interday and intraday coefficients of variation for replicate analyses of spiked serum and urine specimens were less than 6.5%.

The protein binding of nifedipine in concentrations up to 1200 ng ml−1has been measured in serum, pure human albumin solution and pure human α1-acid glycoprotein (AAG) solutions by ultrafiltration. The drug was extensively bound in serum from four healthy volunteers with a mean (±s.d.) fraction bound of 0.992 ± 0.008. In albumin solution (40 g litre−1) the mean (±s.d.) fraction bound 0.970 ± 0.012, was not significantly different (P> 0.05) from that in serum, suggesting that albumin is the major, but not necessarily the only, binding protein for nifedipine in serum. The binding of nifedipine in solutions of A AG was proportional to the AAG concentration and ranged from 0.514 ± 0.059 to 0.755 ± 0.035 in solutions containing 50 and 150 mg% AAG, respectively. Binding of nifedipine in all protein solutions was linear.